Nitrogen substituted acridine have been proposed for use in treatment of senile dementia such as Alzheimer's disease. Such materials are described in U.S. Pat. Nos. 4,631,286; 4,695,573; 4,754,050; 4,816,456; 4,835,275; 4,839,364; 4,999,430; and British Patent Appln. 2,091,249, all of which are hereby incorporated by reference.
Clinical studies have been performed on patients suffering from Alzheimer's disease by utilizing tacrine or 1,2,3,4-tetrahydro-9-acridinaminemonohydrate monohydrochloride (THA). Serum determinations of patients given THA indicated the very rapid formation of THA metabolites. It has also been indicated that elevations of liver enzymes are found in some patients after THA administration, which reportedly can be controlled by adjustment of medication. W. K. Summers, T. H. Tachiki and A. Kling: "Tacrine In The Treatment Of Alzheimer's Disease", EUR. NEUROL. 29 (Supp. 3): 28-32 (1989). Various metabolites of THA have been reported. C. A. Truman, J. M. Ford, C. J. C. Roberts: "Comparison of the Chromatographic Characteristics of Metabolites of Tacrine Hydrochloride in Human Serum and Urine with those of In Vitro Metabolic Products From Hepatic Microsomes", BIOCHEMICAL PHARMACOLOGY, Vol. 42, no. 4, pp. 956-959 (1991). THA is extensively metabolized in animals and man to several monohydroxy and dihydroxy metabolites, some of which are excreted as glucuronide derivatives.
Monooxygenation of chemical materials has been ascribed to cytochromes P450 (P450). These hemoprotein containing monooxygenase enzymes displaying a reduced carbon monoxide absorption spectrum maximum near 450 nm have been shown to catalyze a variety of oxidation reactions including hydroxylation of endogenous and exogenous compounds. M. R. Jachau, "Substrates, Specificities and Functions of the P450 Cytochromes", LIFE SCIENCES, Vol. 47, pp. 2385-2394 (1990). An extensive amount of research has been conducted on the mechanism's by which P450's can catalyze oxygen transfer reactions. B. Testa and P. Jenner, "Inhibitors Of Cytochrome P-450s and Their Mechanism of Action", DRUG METABOLISM REVIEWS, 12(1)1-117 (1981); F. P. Guengerich, "Cytochrome P450: Advances and Prospects", FASEB J., Vol. 6, pp. 667-668 (1992); K. Brosen; M. Murray and C. F. Reidy, "Recent Developments In Hepatic Drug Oxidation Implications For Clinical Pharmacokinetics", CLIN. PHARMACOKINET., 18(3): 220-239, 1990; and M. Murray and G. F. Reidy, "Selectivity in the Inhibition of Mammalian Cytochrome P-450 By Chemical Agents", PHARMACOLOGICAL REVIEWS, 42, 85-101 (1990).
Murray & Reidy, supra, further state that P-450's are ubiquitous enzymes found in the smooth endoplasmic-reticulum as well as mitochondrial fractions of mammalian cells. P450 constitutes a multigene family of enzymes with nearly 150 isoforms identified to date. T. D. Porter and M. J. Coon, "Cytochrome P-450: Multiplicity of Isoforms, Substrates, and Catalytic and Regulatory Mechanisms", J. BIOL. CHEM., Vol. 266, 13469-13472 (1991). The P450 reaction cycle proceeds briefly as follows: initial binding of a substrate molecule (RH) to the ferric form of the cytochrome results in the formation of a binary complex and a shift in the spin equilibrium of the ferric enzyme from the low- to high-spin state. Some evidence has been presented that suggests this configuration more readily accepts an electron from the flavoprotein reductase to form the ferrous P450-substrate complex. However, not all P450s exhibit a relationship between high-spin content and reduction rate. Indeed, it has been proposed that several factors, including the nature of the P450 substrate, the topography of the enzyme/substrate complex, and the potentials of oxidizable atoms each play a role in regulation of the reduction rate. Molecular oxygen binds to the ferrous P450-substrate complex to form the ferrous dioxygen complex which is then reduced by a second electron from the P450 reductase (or perhaps, in some cases, from reduced nicotinamide adenine dinucleotide via cytochrome b.sub.5 and its reductase). Dioxygen bond cleavage in the reduced ferrous dioxygen complex results in the insertion of one atom of oxygen into the substrate, reduction of the other oxygen atom to water, and restoration of the ferric hemoprotein.
Individual members of the P450 family of enzymes and associated mixed function oxidase activities have been described in extrahepatic tissues including brain, adrenal, kidney, testis, ovary, lung and skin. Individual P450s have likewise been characterized in terms of their inducibility by selected chemical classes. Induction of specific P450 enzymes, such as the P450 1A1 and 1A2 subfamily have been extensively studied with respect to regulatory processes of increased mRNA transcription and expression of enzymatic activity. It has been ascertained that materials such as beta-naphthaflavone (beta-NF), 3-methylcholanthrene (3-MC), arochlor 1254 (ACLR) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are materials that have been categorized as inducers of P450 enzymes bearing the designated P450 1A subfamily. At present, two specific P450 enzymes termed 1A1 (nonhepatic) and 1A2 (hepatic) have been characterized by several laboratories. Materials that induce the hepatic P450 1A subfamily of enzymes, and in particular the constitutive 1A2 enzyme include 3-MC, cigarette smoke, beta-NF, TCDD, and ACLR and, in addition, isosafrole, and musk xylenes, are preferential inducers of 1A2. M. Murray and G. F. Reidy, "Selectivity In The Inhibition Of Mammalian Cytochromes P450 By Chemical Agents", PHARMACOLOGICAL REVIEWS, 42, 85-101 (1990); and F. P. Guengerich, "Characterization of Human Microsomal Cytochrome P-450 Enzymes", ANNU. REV. PHARMACOL. TOXICOL. Vol, 29, pp. 241-264 (1989).
It is an object of the present invention to improve the metabolic stability of nitrogen substituted acridines in human body fluids (blood, plasma, brain, liver, etc).
It is an object of the present invention to provide in mammalian body fluids a stable concentration of nitrogen substituted acridine.
It is a further object of the present invention to describe and utilize nitrogen substituted acridines in conjunction with inhibitors of cytochrome P450 1A subfamily (1A1 and 1A2) of enzymes.
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a naphthyridine.
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a xanthine.
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a phenoxy amino alkane.
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a carbamoyl imidazole.
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a guanidine imidazole, e.g. cimetidine (N-cyano-N'-methyl-N"-[2[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]gua nidine)
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a quinoline, e.g. chloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline) and primaquine (8-(4-amino-1-methylbutylamino)-6-methoxyquinoline).
It is a further object of the present invention to describe nitrogen substituted acridines co-administered with a trifluoromethyl oxime ether, e.g., fluvoxamine, also known as 5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl) oxime.
None of the references disclose techniques for maintaining the stability, i.e., non-metabolism of nitrogen substituted acridines, so that they may suitably be effective as agents for treatment of senile dementia.